Multiple sclerosis (MS) is a lifelong debilitating illness with no cures and limited treatment options. Thus new treatments are greatly needed. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we were the first to demonstrate that B cells were required for recovery from disease. These data revealed the potential of harnessing regulatory B cells or Breg for cellular based therapies. However, one major hurdle before this can be accomplished is a better understanding of how Breg control the extent of autoimmune inflammation. We have recently discovered that Breg control both the onset and severity of EAE by the homeostatic maintenance of CD4+Foxp3+ T regulatory cell (Treg) numbers. We found that when B cells were either genetically deficient (?MT) or depleted with anti-CD20 there was a significant reduction in the absolute number of Treg in mice. As for ?MT mice, B cell depletion with anti-CD20 abrogated EAE recovery. Reconstitution of ?MT with WT splenic B cells resulted in the homeostatic expansion of Treg and the subsequent recovery from EAE. These cumulative data solidify a role for Breg in controlling EAE via the maintenance of Treg cell numbers. These data are consistent with the known role of Treg in keeping autoimmune responses in check. When we investigated the mechanism whereby Breg regulate Treg numbers, we discovered that their expression of GITRL and SAP contributed to their ability to promote Treg proliferation and/or promote EAE recovery. The known role for SAP in promoting T cell:B cell interactions in adaptive immune responses suggests that Breg and Treg also directly interact. However, virtually nothing is known regarding the mechanics and biological outcomes of such interactions. When we investigated the phenotype of Breg with the capability of controlling Treg homeostasis we found that a novel population of follicular cells wit IgDlow-neg expression exhibited Breg activity. This population of follicular B cells has never been described indicating that we discovered a novel Breg phenotype. From the above cumulative data, we hypothesize that follicular IgD low-neg Breg control autoimmunity by promoting Treg homeostatic expansion via direct cell-cell interactions facilitated by SAP expression in B cells allowing GITRL:GITR binding promoting Treg proliferation. The testing of this hypothesis will allow us to understand the molecular mechanisms whereby Breg control autoimmunity with the goal of harnessing this knowledge for the development of new therapies. This hypothesis and goal will be achieved in three specific aims: Aim 1: Determine the role of GITRL and SAP in the functional ability of Breg to control Treg homeostasis; Aim 2: Determine the mechanism whereby SAP facilitates Breg:Treg interactions and Aim 3. Characterization and functional analysis of a novel IgDlow-neg follicular Breg.